The development of the benzodiazepines has been a great advance in the pharmacologic management of anxiety. They have also replaced barbiturates as the sedative-hypnotic drugs of choice. The benzodiazepines, unlike the barbiturates, are not complete CNS depressants and even at high doses are rarely associated with lethal respiratory depression or vasomotor collapse. True addiction to benzodiazepine compounds is also very rare. In addition, depending upon the drug, benzodiazepines possess anticonvulsant and muscle relaxant properties as well.
Mechanisms of action There is growing evidence that gamma-aminobutyric acid (GABA), an inhibitory amino acid neurotransmitter, may play a central role in the brain mechanism(s) of anxiety. Benzodiazepines selectively, but indirectly, enhance GABA neurotransmission, possibly by increasing neuronal receptor sensitivity to GABA. Also, a close interaction has been described between GABA and benzodiazepine receptor binding, which involves the neuronal chloride ionophore channel. Despite these observations, the specific mechanism by which benzodiazepines mediate their clinical effects is not completely understood.
Clinical conditions in which anxiolytic medications are used The antianxiety medications are most effective in the management of relatively short-lived reactive states of tension and anxiety and are the drugs of choice in the treatment of generalized anxiety disorders. The anxiolytic benzodiazepines are useful in treating panic disorders but are not the drugs of choice, although alprazolam at higher doses (4 to 10 mg) can block panic attacks. Rather, it is the TCA and MAO inhibitor antidepressants which are the drugs of choice to suppress symptoms of panic disorder. However, the anxiolytics may have a role in the treatment of anticipatory anxiety, which is almost always present in patients with panic disorders. Sometimes, both a TCA and a benzodiazepine anxiolytic may be necessary in the treatment of panic disorder. The anxiolytics are also useful in the treatment of anxiety symptoms that accompany phobic disorders.
Clinical use of the antianxiety medications Clinically the benzodiazepines are divided on the basis of their use as either primarily anxiolytics or sedative-hypnotics. The more commonly prescribed drugs are listed along with the usual oral dose ranges. The pharmacokinetic characteristics of many of the benzodiazepines are complicated by long drug elimination half-lives and the metabolic conversion of parent compounds to active metabolites. Diazepam is converted to the active metabolite desmethyl-diazepam (nordiazepam) which, in turn, can be hydroxylated to yield oxazepam, also a potent benzodiazepine. This metabolic pathway extends the activity half-life of diazepam threefold. The hypnotic flurazepam is converted to its active metabolite N-l-desalkylflur-azepam, whose half-life is more than 48 h; hence, repetitive daily doses given in excess of a week or two can result in the accumulation of the active metabolites of the drug. Prazepam has metabolic compounds identical to those of diazepam and has a similar drug elimination half-life. Oxazepam and lorazepam, both of which undergo glucuronide conjugation, have no active metabolites and therefore have the advantage of a shorter half-life. The benzodiazepines temazepam, triazolam, and alprazolam also have the advantage of shorter half-lives and to date, no long-acting active metabolites have been identified.
Diazepam has been the standard against which all anxiolytic drugs are measured, and no other anxiolytics have demonstrated better antianxiety potency. The newly developed benzodiazepines appear equally effective and have eliminated certain of the undesirable side effects. Specifically, lorazepam, oxazepam, and alprazolam are without active metabolites and cumulative effects of daytime sedation are less noticeable.
Treatment regimens usually last 4 weeks or less and medications are prescribed continually for 7 to 10 days followed by a 2- to 3-day drug holiday; then this sequence is repeated. This helps avoids the development of tolerance to the anxiolytic effects. The shorter-acting medications (lorazepam, alprazolam, etc.) are prescribed in a three or four times daily regimen, and the longer-acting drugs (diazepam, etc.) are given in a single dose or a twice daily regimen. For example, it is common practice to prescribe one dose of diazepam at bedtime, since it will both promote sleep and reduce anxiety levels during the following day.
In prescribing the anxiolytic benzodiazepines clinicians should avoid the possibility of habituating patients to chronic benzodiazepine use. One of the earliest signs is the development of tolerance, where the patient repeatedly requests escalations in drug dose. Since benzodiazepines do produce mild euphoria and a sense of well-being, anxious patients often want to preserve this feeling and request additional medication. On the other hand, clinical surveys of prescription practices have shown that clinicans are aware of the problems of benzodiazepine habituation and sometimes respond by being too cautious and by unnecessarily undertreating patients. The use of the drug holiday treatment regimen described above and the physician’s resistance to repetitively increasing dosage will help to minimize the problem of drug habituation.
In addition to its role as an anxiolytic, diazepam is also the drug of choice in this class for muscle relaxation and for the treatment of alcohol withdrawal syndromes. It is the benzodiazepine of choice for intractable seizures. Oxazepam, because of the nonaccumulation of active metabolites, is a good choice for anxiolysis in the elderly.
Side effects and interactions with other drugs The most important adverse effect of the benzodiazepines is the discomfort caused by the withdrawal syndrome, which can occur after chronic treatment. While there is very little risk of physiologic dependence on these drugs when used appropriately, the withdrawal symptoms do contribute to the development of psychological habituation. Between 40 and 50 percent of patients develop minor withdrawal symptoms after cessation of chronic benzodiazepine treatment. Symptoms include muscle aches, agitation, restlessness, insomnia, and generalized anxious dysphoria. In some patients more serious CNS withdrawal symptoms may appear, including confusional and delirium states and, more rarely, grand mal seizures. Rebound anxiety can also be seen in patients with anxiety disorders but is less prevalent when benzodiazepines with long-acting metabolites are used and less frequent if the drug is gradually discontinued. Risk for withdrawal increases with the length of the treatment and is reported with much greater frequency (e.g., more than 90 percent) among patients who have been treated for 1 year or more. Withdrawal symptoms occur within the first 24 to 48 h after cessation of drug use in the short-acting benzodiazepines, but in those benzodiazepines with long-acting metabolites (e.g., diazepam, chlordiazepoxide), the withdrawal symptoms can occur 4 to 6 days and even longer after drug cessation. With the usual recommended dosage regimens and the gradual withdrawal technique (e.g., over 3 to 4 weeks), the appearance of a withdrawal syndrome in patients can be minimized significantly. While there is little true addiction potential, patients should be on these medications for only as long as necessary.
The most common minor side effects are daytime sedation, mild cognitive impairment, motor clumsiness and, with some drugs, specific memory decrements (e.g., lorazepam). Another rare but troublesome side effect from some benzodiazepines is paradoxical emotional responses, primarily manifested as aggressive and impulsive behavior.
Unlike barbiturates, the benzodiazepines do not noticeably induce hepatic microsomal enzyme activity and therefore do not affect the metabolism of other medications. Their primary interaction with other drugs is their additive effects with other CNS depressants. The cross-tolerance with ethanol has made the benzodiazepines ideal medications for the treatment of alcohol withdrawal syndromes. Patients should be cautioned that ethanol is potentiated by benzodiazepines and this combination ought to be avoided.
The newer anxiolytic medications It has been established that certain beta-adrenergic blocking agents, such as propranolol, can dampen the peripheral physiologic symptoms of anxiety. Initially, it was felt that these drugs might be better nonsedative anxiolytic compounds, but this has not held up in controlled studies. While propranolol does attenuate somatic manifestations of anxiety (e.g., palpitations, tremor), it appears to have lesser effects on the psychological components (e.g., intense fearfulness). Although propranolol has been used in the treatment of severe cases of fear of public speaking and in musicians (oral dose 40 to 320 mg qd), it is not a comprehensively effective anxiolytic. It is possible that with additional study other peripheral blocking agents may prove to be more effective.
A new class of anxiolytic drugs, the azaspirodecanediones, has been developed. One of the first compounds studied clinically is buspirone. It has little structural similarity to other anxiolytics or even to other psychotropics. It is not anticonvulsant, does not interact with the putative benzodiazepine receptor, is not cross-tolerant to other CNS depressants, and no abstinence syndrome has yet been described. In several controlled trials it has proved to be an effective anxiolytic with relatively less sedation and decrements in psychomotor performance. To date it has not been extensively studied and it is possible that efficacy problems and as yet unidentified side effects may be associated with its use.
In addition to their efficacy in panic and phobic disorders, there are controlled studies reporting that tricyclic antidepressants are anxiolytics as effective as the benzodiazepines in generalized anxiety disorders. It is possible that continued investigations will identify a broader role for TCAs in the treatment of the full spectrum of anxiety disorders.